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J. Biol. Chem., Vol. 282, Issue 2, 1205-1215, January 12, 2007

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G Protein-coupled Receptor Kinase 2-mediated Phosphorylation of Downstream Regulatory Element Antagonist Modulator Regulates Membrane Trafficking of Kv4.2 Potassium Channel^*

Ana Ruiz-Gomez¹, Britt Mellström¹, Daniel Tornero^¶1, Esperanza Morato, Magali Savignac, Helena Holguín, Koldo Aurrekoetxea, Paz González, Carmen González-García^¶, Valentín Ceña^¶, Federico Mayor, Jr., and Jose R. Naranjo²

From the Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa" Universidad Autonoma de Madrid-Consejo Superior de Investigaciones Científicas, Campus de Cantoblanco, 28049 Madrid, Spain, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, C/Darwin 3, 28049 Madrid, Spain, and ^¶Unidad Asociada Neurodeath, Universidad Castilla La Mancha-Consejo Superior de Investigaciones Científicas, Avenida Almansa, s/n, 02006 Albacete, Spain

Downstream regulatory element antagonist modulator (DREAM)/potassium channel interacting protein (KChIP3) is a multifunctional protein of the neuronal calcium sensor subfamily of Ca²⁺-binding proteins with specific roles in different cell compartments. In the nucleus, DREAM acts as a Ca²⁺-dependent transcriptional repressor, and outside the nucleus DREAM interacts with Kv4 potassium channels, regulating their trafficking to the cell membrane and their gating properties. In this study we characterized the interaction of DREAM with GRK6 and GRK2, members of the G protein-coupled receptor kinase family of proteins, and their phosphorylation of DREAM. Ser-95 was identified as the site phosphorylated by GRK2. This phosphorylation did not modify the repressor activity of DREAM. Mutation of Ser-95 to aspartic acid, however, blocked DREAM-mediated membrane expression of the Kv4.2 potassium channel without affecting channel tetramerization. Treatment with the calcineurin inhibitors FK506 and cyclosporin A also blocked DREAM-mediated Kv4.2 channel trafficking and calcineurin de-phosphorylated GRK2-phosphorylated DREAM in vitro. Our results indicate that these two Ca²⁺-dependent posttranslational events regulate the activity of DREAM on Kv4.2 channel function.

Received for publication, July 27, 2006 , and in revised form, November 9, 2006.

^* This work was supported by grants from the Ministerio de Educación y Ciencia (to F. M., J. R. N., B. M., and C. G.-G.), Fondo Investigaciones Sanitarias de la Seguridad Social (to J. R. N., V. C., and C. G.-G.), Fundación Ramón Areces (to F. M.), Fundación La Caixa (to J. R. N. and V. C.), and Comunidad Autónoma de Madrid (to J. R. N. and B. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally.

² To whom correspondence should be addressed. Tel.: 34-91-5854682; Fax: 34-91-5854506; E-mail: naranjo{at}cnb.uam.es.

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